The present invention provides a drug delivery system for the oral administration of a hydrophobic active ingredient. The active ingredient""s post-ingestion dissolution rate and its corresponding bioavailability can be optimized by intimately mixing a micronized hydrophobic drug with suitably sized inert particles to form a dispersion that will facilitate desired bioavailability.
Drug efficacy depends upon its bioavailability to the patient. For drugs that are hydrophobic or poorly soluble in water, increased wettability upon exposure to biological fluids can become a goal for those formulating and manufacturing these agents.
For example, the bioavailability of pharmacologically active entities that are hydrophobic may be enhanced by reduction of particle size. See, e.g., Mortada and Mortada 28 (4) Acta Pharm. Tech. 297-301 (1982); U.S. Pat. No. 4,344,934, Martin et al.; WO 90/04962, Nystrom et al. Such micronization of an active principle may improve the dissolution of the active principle in vivo, and thus improve its bioavailability, but the agglomeration of the micronized particles can diminish these characteristics.
Alternatively, the use of a surfactant, such as sodium lauryl sulfate, in a formulation of an active principle may improve absorption of the drug, and hence improve its bioavailability. For example, the co-micronization of an active ingredient with a solid surfactant to improve a water-insoluble drug""s in vivo bioavailability has been described. U.S. Pat. No. 4,895,726, Curtet, et al. The present invention minimizes the use of surfactants, thus avoiding possible reactivity or sensitivity to the surfactant.
Microcrystalline cellulose has been used as an excipient in the manufacture of pharmaceuticals. See, e.g., El-Samaligy et al., 31 Int""l J. Pharma. 137-44 (1986). However, it reportedly interfered with the bioavailability, or reduced the activity, of ampicillin and amoxycillin when used as a carrier. Id. On the other hand, microcrystalline cellulose has been mixed with diethylstilbestrol to improve the dispersability of that hydrophobic drug in animal feed. U.S. Pat. No. 3,639,637, Campbell. Microcrystalline cellulose has also been included as an excipient in formulations comprising water-soluble n-acetyl-p-aminophenol and fumed silica. U.S. Pat. No. 4,013,785, Weintraub et al.
In one embodiment, this invention can provide for improved wettability of hydrophobic pharmaceutical agents upon exposure to biological fluids. The inventors of the present invention discovered unexpectedly that the dispersion achieved by intimately mixing a micronized hydrophobic drug with inert particles of suitable size, such as lactose or microcrystalline cellulose, and, optionally, other suitable substrates, increases the dissolution rate of the drug and hence improves its bioavailability. The intimate mixing and maximized dispersion of the micronized drug with a material of small particle size and irregular surface area, such as microcrystalline cellulose or lactose, can separate active agglomerates and disperse them to the substrate surface, resulting in a lower surface tension thereby improving wettability upon exposure to biological fluids.
A capsule formulation, including the carrier particle and hydrophobic active ingredient, may be manufactured by intimately mixing the micronized active ingredient(s) with the suitably sized particles, such as lactose or microcrystalline cellulose, with or without a disintegrant or other excipients, for a period of time sufficient to maximize dispersion of the active ingredient to the carrier. Dispersion may be monitored optically, for example. The granulate mixture is then wetted with an appropriate granulation solution, with or without surfactant or other excipients. After the wet granules are dried, they are milled to desirable granule size. The milled granules may be blended with a suitable lubricant or other non-lubricant excipient. The final blend is then filled into capsules of suitable size.
An objective of the present invention is a drug delivery system comprising a micronized hydrophobic drug and an inert substrate of suitable particle size. In a particular aspect of the invention, the inert substrate is microcrystalline cellulose. In another aspect of the invention, the inert substrate is lactose. In a preferred embodiment of the invention, the inert substrate has a mean particle size of about 1 micron to 500 microns in size. More preferably, the inert substrate has a mean particle size of less than about 50 microns.
Another object of the invention provides a drug delivery system in which the active ingredient is micronized fenofibrate or an acceptable salt of fenofibrate. In another object of the invention, the drug delivery system includes fenofibrate and an inert substrate of suitable size, such as microcrystalline cellulose or lactose.
In a preferred embodiment of the invention, the ratio of the inert substrate to the hydrophobic drug is between 0.1 and 10.0. More preferably, the ratio of the inert substrate to the hydrophobic drug is between about 0.1 and 4.0. Most preferably, the ratio of the inert substrate to the hydrophobic drug is between about 0.3 and 2.0. In another preferred embodiment, the inert substrate is microcrystalline cellulose. In an alternative preferred embodiment, the inert substrate is lactose.
Another objective of the present invention is a method of improving the bioavailability of a hydrophobic drug, comprising the steps of micronizing said hydrophobic drug and mixing it with an inert substrate of suitable particle size until the drug is optimally dispersed with the inert material.
Still another objective of the present invention provides for a method for treating high cholesterol by administering to a patient in need thereof a pharmaceutical composition comprising fenofibrate and either microcrystalline cellulose or lactose.
The present invention also provides for a method of preparing a pharmaceutical composition with increased bioavailability of a hydrophobic active ingredient, by mixing intimately that active ingredient with an inert substance of suitable particle size until desired dispersion is achieved, wet-granulating the mixture in the presence of solvent, drying the wet granules, milling the dried granules to desirable granule size, blending the milled granules with a lubricant, and filling the milled granules into a capsule of suitable size. In one aspect of this embodiment, the particles are lactose. In another aspect, the particles are microcrystalline cellulose. Another aspect of this embodiment includes adding a disintegrant to the formulation. Another aspect includes adding a surfactant to assist in wetting the mixture.